Autoimmunity - Is it possible to be too clean

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Autoimmunity - Is it possible to be too clean

16 Apr 2004

A group of scientists at The Scripps Research Institute have found a

connection between poor T cell survival in the body and the development of

autoimmunity, they ask whether autoimmunity is also a question of being too

clean.

On the basis of this connection, the scientists are proposing a new

hypothesis about the cause of autoimmunity, in which components of a

person's immune system attack his/her own tissues leading to diseases such

as Type 1 diabetes and rheumatoid arthritis.

" Autoimmunity has [traditionally] been considered a condition of too much

stimulation, " says Scripps Research Immunology Professor Nora Sarvetnick,

Ph.D. " What we are seeing is that it is a condition of too little

stimulation. "

In an article appearing in this week's issue of the journal Cell, Nora

Sarvetnick and her coauthors in the Department of Immunology assert that we

need a certain level of immune stimulation to fill the body with immune

cells. An understimulated immune system results in too few T cells, and the

body tries to correct this by inducing a vigorous expansion of the remaining

T cells, creating a more autoreactive population.

The hypothesis explains why childhood bacterial infections decrease the risk

for developing autoimmune diseases and explains why autoimmunity has been

rising in the last half century in populations with decreased exposure to

pathogens.

It also provides a new way for thinking about how to make autoimmune

diseases more preventable. The key to decreasing the chances of developing

autoimmunity may be to stimulate the immune system by priming people with

germs.

Autoimmunity and Lymphopenia

Autoimmune diseases are to biology as friendly fire is to war.

Normally, the body's immune system is designed to recognize invading viruses

or bacteria and destroy them. But in autoimmune diseases, the body's

response is not limited to pathogens. Instead, the body manufactures cells

and molecules that attack its own tissues and organs. This assault can have

severe consequences for health and can be lethal.

Take Type 1 (insulin-dependent) diabetes mellitus, for instance. Type 1

diabetes manifests when T cells become autoreactive and attack and kill beta

cells in the pancreas, the body's source of insulin. Without insulin, the

glucose in the bloodstream increases and is maintained at levels much

greater than normal.

Over time, this can lead to nerve and kidney damage, reduced eyesight, and

an increased risk of developing heart disease and vascular degeneration.

Before the discovery and isolation of insulin in the 1920s, having this type

of chronic metabolic disease meant certain death. Today, insulin is a

reasonable treatment, but Type 1 diabetes is still a chronic infection for

which there is no prevention and no cure.

According to the new hypothesis that Nora Sarvetnick and her colleague

Cecile King, Ph.D. are proposing, the root cause of autoimmunity is a

failure to make an adequate response to an infection, in other words, an

immune system that is not working hard enough (one that is hyporesponsive).

This hyporesponsiveness creates a condition known as lymphopenia, where

there is a reduction in the number of T cells in the body. Often people with

autoimmune diseases like Type 1 diabetes, lupus, and rheumatoid arthritis

have low T cell numbers.

If the body detects low levels of T cells, it resorts to homeostatic

expansion, a mechanism that has never been associated with autoimmunity

before. Under homeostatic expansion, growth signals stimulate the existing T

cells in the body to divide and multiply.

This homeostatic process should normally fill the body, but sometimes that

does not happen due to disrupted growth signals or a viral infection that

causes the number of T cells to go down even as the body is trying to

increase their numbers. These are the conditions that lead to autoimmunity,

says Sarvetnick.

Insidious Division

In their current study, Sarvetnick, King, and their colleagues look at the

immune systems of a type of mouse called NOD, which is genetically prone to

developing diabetes. The NOD mouse has a genetic defect that causes it to

produce excessive amounts of a molecule called interleukin-21, which signals

the growth of T cells without signaling for their survival.

Normally, T cells undergoing homeostatic expansion receive both signals to

grow and signals to stay alive. Since the NOD mice cannot provide adequate

amounts of these latter signals, their T cells proliferate furiously but do

not survive long term. The NOD mouse's cells turn over too rapidly, leaving

them with lymphopenia, a dearth of T cells.

The body tries to fill the void, and this filling leads to what Sarvetnick

terms insidious division.

The high turnover of T cells presents a selective pressure that favors the

growth of T cells that best recognize the tissue nearest to where the

division is taking place, in other words, the T cells with the best chance

of survival tend to be the ones that are skewed to recognize self tissue.

Thus, these survivors have a tendency towards autoreactivity, which can lead

to autoimmunity later on when these cells become activated ¡§effector¡¨

cells.

An analogous process is believed to occur when a viral infection causes

lymphopenia. Sarvetnick and other scientists believe that Type 1 diabetes is

often initiated by a common virus that infects cells in the pancreas.

During the viral infection, the body makes an adaptive immune response, and

killer T cells selectively target and eliminate other cells in the body that

are infected with the virus. However, the T cells themselves are often lost.

Diabetes develops when there is a rapid turnover of T cells, and the

resulting T cell population targets insulin-producing beta cells.

The Benefits of a Bacterial Swill

In their paper, Sarvetnick and her colleagues showed that NOD mice can be

protected against diabetes by challenging them with a swill of bacterial

cell wall components called CFA, which increased the T cell count and

curtailed the development of diabetes in the mice.

To show that this effect was due to the increase in T cell count following

the CFA administration and not some other cause, they passively stimulated

the immune systems of NOD mice by infusing them with T cells. These

infusions also prevented the NOD mice from developing diabetes.

According to Sarvetnick's and King's hypothesis, the protection against

diabetes results from exposure to these pathogens because it keeps the body

full of immune cells. Increased numbers of T cells act as a buffer against

the emergence of self-reactive T cells by shutting down homeostatic

expansion.

This hypothesis could explain a discrepancy in the number of cases of

autoimmune disease in developed and developing countries. Disease rates have

been on the rise in developed countries in the last 50 years compared to

their developing neighbors, presumably because people in less developed

countries are exposed to more pathogens.

" The cleaner everyone is, the less stimulation their immune system gets, "

says Sarvetnick. " Their immune system tends to be incomplete. "

The article, " Immune insufficiency generates autoimmunity " is authored by

Cecile King, Ilic, Kersten Koelsch, and Nora Sarvetnick and appears in

the April 16, 2004 issue of the journal Cell. After April 16, the article

will be available online at http://www.cell.com/.

The research was funded by the National Institutes of Health and the

Juvenile Diabetes Foundation International.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the

world's largest, private, non-profit biomedical research organizations. It

stands at the forefront of basic biomedical science that seeks to comprehend

the most fundamental processes of life. Scripps Research is internationally

recognized for its research into immunology, molecular and cellular biology,

chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and

synthetic vaccine development.

Contact: S. Bardi

jasonb@...

858-784-9254

Scripps Research Institute